US20040063682A1 - Preparation of aztreonam - Google Patents

Preparation of aztreonam Download PDF

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US20040063682A1
US20040063682A1 US10/635,659 US63565903A US2004063682A1 US 20040063682 A1 US20040063682 A1 US 20040063682A1 US 63565903 A US63565903 A US 63565903A US 2004063682 A1 US2004063682 A1 US 2004063682A1
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aztreonam
acid
amino
aqueous
product
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Viktor Gyollai
Erzsebet Meszaros Sos
Csaba Szabo
Claude Singer
Szabolcs Salyi
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Teva Pharmaceutical Works PLC
Teva Pharmaceuticals USA Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the synthesis of Aztreonam. Specifically, the process entails hydrolyzing [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (t-Bu Aztreonam) to form Aztreonam.
  • Aztreonam is a monobactam antibiotic disclosed in U.S. Pat. No. 4,775,670, which is incorporated by reference herein in its entirety.
  • Aztreonam has the chemical name (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,-3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid.
  • Aztreonam is also known as [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid and (2S, 3S)-3-[[2-[2-amino-4-thiazolyl]-(Z)-2[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidine-1-sulfonic acid.
  • Aztreonam has the structure:
  • Aztreonam is known to exist in various polymorphic forms including the ⁇ , ⁇ , ⁇ , and ⁇ forms.
  • the process includes acylating a compound of formula IV:
  • the acylation entails reacting a compound of formula IV with a carboxylic acid or the corresponding carboxylic acid halide or carboxylic acid anhydride (R 1 —OH) in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole.
  • U.S. Pat. No. 4,775,670 discloses that when the acyl group (R 1 ) contains reactive functional groups, such as amino or carboxyl groups, it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting product. The deprotection is carried out by reaction of the acylation product with trifluoroacetic acid in the presence of anisole under anhydrous
  • U.S. Pat. No. 4,946,838 discloses a process for making crystalline anhydrous Aztreonam comprising reacting the diphenylmethyl ester of Aztreonam ([3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid) with trifluoroacetic acid in the presence of anisole under anhydrous conditions to produce the ⁇ -form of Aztreonam.
  • the ⁇ -form is recrystallized from an anhydrous organic solvent to produce the ⁇ -form of Aztreonam.
  • the ⁇ -form is anhydrous, substantially non-hygroscopic and more stable than the ⁇ -form.
  • R is acyl.
  • the process comprises acylating azetidin with 2-(2-amino-4-thiazolyl)-2-(Z)-(alkoxyimino) acetic acid in the presence of 1-hydroxy-benzotriazole and dicyclohexylcarbodiimide.
  • U.S. Pat. No. 5,194,604 discloses a process and intermediates for making beta-lactams having aminothiazole(iminooxyacetic acid)acetic acid sidechains of formula (I), such as Aztreonam.
  • the process comprises acylating a compound of formula III:
  • [0016] is a 4, 5, 6 or 7 membered heterocyclic ring having at least one nitrogen atom in the ring or such a group fused to a phenyl or substituted phenyl ring, to form a compound of formula (I):
  • R 1 -R 6 are as defined in U.S. Pat. No. 5,194,604.
  • Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom
  • R 1 may be lower alkoxycarbonyl-lower alkyl
  • R 2 may be lower alkyl.
  • R 20 equals R 2 and R 3 is hydrogen or sulpho, with a thioester of the formula (III):
  • R 10 has any of the values of R 1 .
  • U.S. Pat. No. 4,652,651 discloses that where R10 is a lower alkoxycarbonyl-lower alkyl group, for example the t-butoxycarbonylmethyl group, this can be converted, if desired, into the corresponding carboxylower alkyl group by treatment with a strong acid such as trifluoroacetic acid (optionally in the presence of anisole), hydrochloric acid or p-toluenesulphonic acid at a low temperature such as ⁇ 10° C. to room temperature.
  • a strong acid such as trifluoroacetic acid (optionally in the presence of anisole), hydrochloric acid or p-toluenesulphonic acid at a low temperature such as ⁇ 10° C. to room temperature.
  • the invention is based on the discovery that Aztreonam can be produced by reacting [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid with aqueous acid.
  • the process of the invention enables yields of between 70-75% and purities above 98%, preferably above 99%.
  • the inventive aqueous process is advantageous over the prior art anhydrous processes in that the reaction conditions are more mild, there is no need to clean the final product and there is no need to keep the system dry. Thus, the aqueous process is less expensive than the anhydrous processes.
  • the present invention is directed to a process for preparing [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid by hydrolyzing the ester group of [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid.
  • the hydrolysis may be effected by reacting the ester with aqueous acid, at elevated temperatures.
  • the invention is directed to a process for making Aztreonam comprising reacting [3S-[3 ⁇ (Z),4 ⁇ ]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid also known as (t-Bu Aztreonam and Aztreonam t-butyl ester) with an aqueous acid at elevated temperatures.
  • the aqueous acid is preferably a mineral acid, such as hydrochloric acid or sulfuric acid, of various concentration.
  • the aqueous mineral acid is preferably more concentrated than 0.1 mol/l.
  • the aqueous acid is a 1:1 v/v HCl:water mixture.
  • Aqueous trifluoroacetic acid may also be used in various concentrations.
  • the hydrolysis reaction is carried out at elevated temperatures, preferably 40° C. or greater, more preferably between 50 and 80° C., and most preferably between 60 and 70° C.
  • the Aztreonam t-butyl ester can be obtained by reacting Azetidin, (3S,4S)-3-Amino-4-methyl-2-oxo-azetidine-1-sulfonic acid, with TAEM ((Z)-2-(2-Aminothiazole-4-yl)-2-(t-butoxycarbonyl)-isopropoxyimino acetic acid, benzothiazole-2-yl-thiolester), as illustrated in Examples 1 and 2.
  • Azetidin is dissolved in 20 ml acetonitrile (or dimethyl formamide) with the assistance of 5 ml of triethylamine at room temperature. The solution is cooled to 0° C. A solution of 4 g TAEM in 25 ml THF is added with magnetic stirring. If the color disappears, 8 g TAEM in 50 ml THF is added. After 10 minutes, another 4.1 g TAEM in 25 ml THF is added. The solution is stirred at 0° C. for an additional hour. The pH is adjusted to about 4-5 with a freshly prepared TFA solution (TFA-THF 1:4, V/V).
  • the THF is evaporated (weight loss is about 90 g) at 30° C. under vacuum.
  • the remaining residue is diluted with 200 ml ethylacetate and then extracted with 100 ml and then 50 ml of distilled water.
  • the aqueous extracts are combined and washed twice with 50 ml ethylacetate after readjustment of the pH to about 4-5.
  • the dissolved ethylacetate is removed from the aqueous phase by vacuum at 30° C. 10-15 g KCl (or NaCl) is dissolved.
  • the solution is acidified with HCl solution (cc. HCl-distilled water 1:4, V/V) with stirring (approx. 10 ml).
  • the solution is cooled to 0° C. with slow stirring and crystallization occurs.
  • the resulting suspension is refrigerated overnight (at about 5° C.).
  • the suspension is filtered on a glass filter, and the crystals are washed with chilled water.
  • the washed crystals are dried at room temperature.
  • the product, Aztreonam t-butyl ester is about 12.5-13 g white solid, which is sufficiently pure for the next step.
  • Azetidine is dissolved in a mixture of 240 ml acetonitrile and 60 ml triethylamine. When dissolution is complete, TAEM is added in four portions. The suspension is stirred for 20-30 min, then diluted with 500 ml EtOAc and 500 ml water and stirred for 5-10 min. The pH of the emulsion is set to 5 with 2.4 M HCl solution. After the phases separate, the pH of the aqueous phase is checked. If the pH is between 4.20 and 5.30, the two phases are filtered and separated, otherwise more HCl is added. The upper phase is diluted with 900 ml ethylacetate and extracted with 2 ⁇ 500 ml water (faster phase separation).
  • the combined aqueous phase is diluted with 500 ml water and washed with 2 ⁇ 500 ml ethylacetate.
  • the dissolved ethylacetate is removed from the aqueous phase by vacuum.
  • the aqueous phase is acidified further to pH 2 with 2.4 M HCl solution.
  • the solution is stirred and cooled. Crystallization starts soon.
  • the suspension is stirred and cooled to 0° C., stirring at this temperature overnight.
  • the suspension is filtered, washed with chilled water, dried at 38° C. in air-circulated oven for 3 h.
  • the yield is approx. 116-120 g of Aztreonam t-butyl ester.
  • Aztreonam t-butyl ester (113.6 g, 0.231 mol) is suspended in 975 ml water at 60° C. with stirring and 325 ml trifluoroacetic acid is added. The solution is stirred for 60 min., then it is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 240 ml chilled water and filtered again. The filtrate is re-suspended in 360 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 61.6 g Aztreonam (water content: 15-16%).
  • Aztreonam t-butyl ester (18.0 g, 0.0366 mol) is suspended in 144 ml water at 60° C. with stirring and 40 ml aqueous hydrochloric acid (1:1, V/V) is added. The solution is stirred for 60 min, then 37 ml 5.4 M NaOH solution is added. The solution is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 50 ml chilled water and filtered again. The filtrate is re-suspended in 70 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 8.3 g Aztreonam (water content: 15-16%). The crude Aztreonam is crystallized.
  • Aztreonam t-butyl ester (100.00 g, Assay as is: 97.2%, 0.19796 mol)) is suspended in a mixture of 450 ml water and 5 ml trifluoroacetic acid. The suspension, which slowly becomes clear, is heated to 58° C. with stirring and 100 ml trifluoroacetic acid is added. The solution is stirred for 105 min at 60-63° C. The solution is added to chilled water (450 ml) with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 18 hours. The product is filtered on a glass-filter and washed with 300 ml chilled water.
  • the product is suspended in 650 ml chilled water, then filtered and washed with 300 ml cold acetone.
  • the product is suspended in 400 ml cold acetone and filtered and dried in an air-ventilation oven at 30° C. for 30 min. Yield: 66.6 g (63%, according to assays) Aztreonam (Assay: 100.5%, water content: 18.0%).
  • Aztreonam t-butyl ester (27.11 g, Assay as is: 96.5%, 0.05328 mol) is suspended in a mixture of 122 ml water and 1.35 ml cc. HCl. The suspension is heated to 62° C. with stirring and 30 ml cc. HCl is added. The suspension, which becomes clear after approx. 15 min, (then the product starts to precipitate), is stirred for 30 min at 63-65° C. Chilled water (162 ml) is added with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 2 hours.

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  • Chemical & Material Sciences (AREA)
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Abstract

The invention relates to a process for the synthesis of Aztreonam Specifically, the process entails hydrolyzing [3 S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (t-Bu Aztreonam) to form Aztreonam.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit under 35 U.S.C. §119(e) of provisional application Serial Number 60/400,699, filed Aug. 5, 2002 and provisional application Serial Number 60/401,749, filed Aug. 8, 2002, both of which are incorporated herein by reference.[0001]
    • FIELD OF THE INVENTION
  • The present invention relates to a process for the synthesis of Aztreonam. Specifically, the process entails hydrolyzing [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (t-Bu Aztreonam) to form Aztreonam. [0002]
    • BACKGROUND OF THE INVENTION
  • Aztreonam is a monobactam antibiotic disclosed in U.S. Pat. No. 4,775,670, which is incorporated by reference herein in its entirety. Aztreonam has the chemical name (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,-3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. Aztreonam is also known as [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid and (2S, 3S)-3-[[2-[2-amino-4-thiazolyl]-(Z)-2[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidine-1-sulfonic acid. [0003]
  • Aztreonam has the structure: [0004]
    Figure US20040063682A1-20040401-C00001
  • Aztreonam is known to exist in various polymorphic forms including the α, β, δ, and γ forms. [0005]
  • U.S Pat. No. 4,775,670 discloses a process for making Aztreonam, a compound of formula I: [0006]
    Figure US20040063682A1-20040401-C00002
  • The process includes acylating a compound of formula IV: [0007]
    Figure US20040063682A1-20040401-C00003
  • The acylation entails reacting a compound of formula IV with a carboxylic acid or the corresponding carboxylic acid halide or carboxylic acid anhydride (R[0008] 1—OH) in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ such as N-hydroxybenzotriazole. U.S. Pat. No. 4,775,670 discloses that when the acyl group (R1) contains reactive functional groups, such as amino or carboxyl groups, it may be necessary to first protect those functional groups, then carry out the acylation reaction, and finally deprotect the resulting product. The deprotection is carried out by reaction of the acylation product with trifluoroacetic acid in the presence of anisole under anhydrous conditions.
  • Similarly, U.S. Pat. No. 4,946,838 discloses a process for making crystalline anhydrous Aztreonam comprising reacting the diphenylmethyl ester of Aztreonam ([3S-[3β(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid) with trifluoroacetic acid in the presence of anisole under anhydrous conditions to produce the α-form of Aztreonam. The α-form is recrystallized from an anhydrous organic solvent to produce the β-form of Aztreonam. The β-form is anhydrous, substantially non-hygroscopic and more stable than the α-form. [0009]
  • U.S. Pat. No. 5,254,681 discloses a process for preparing monobactams of formula (I): [0010]
    Figure US20040063682A1-20040401-C00004
  • wherein R is acyl. The process comprises acylating azetidin with 2-(2-amino-4-thiazolyl)-2-(Z)-(alkoxyimino) acetic acid in the presence of 1-hydroxy-benzotriazole and dicyclohexylcarbodiimide. [0011]
  • U.S. Pat. No. 5,194,604 discloses a process and intermediates for making beta-lactams having aminothiazole(iminooxyacetic acid)acetic acid sidechains of formula (I), such as Aztreonam. The process comprises acylating a compound of formula III: [0012]
    Figure US20040063682A1-20040401-C00005
  • with a compound of formula (II): [0013]
    Figure US20040063682A1-20040401-C00006
  • in which R[0014] 7 is
    Figure US20040063682A1-20040401-C00007
  • wherein [0015]
    Figure US20040063682A1-20040401-C00008
  • is a 4, 5, 6 or 7 membered heterocyclic ring having at least one nitrogen atom in the ring or such a group fused to a phenyl or substituted phenyl ring, to form a compound of formula (I): [0016]
    Figure US20040063682A1-20040401-C00009
  • wherein R[0017] 1-R6 are as defined in U.S. Pat. No. 5,194,604.
  • U.S. Pat. No. 4,652,651, which is incorporated by reference herein in its entirety, discloses a process for making 1-sulpho-2-oxoazetidine derivatives of the formula (I): [0018]
    Figure US20040063682A1-20040401-C00010
  • in which Het is an optionally amino-substituted, 5- or 6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms and optionally also an oxygen or sulphur atom, R[0019] 1 may be lower alkoxycarbonyl-lower alkyl and R2 may be lower alkyl. The process entails acylating a compound of formula (II):
    Figure US20040063682A1-20040401-C00011
  • in which R[0020] 20 equals R2 and R3 is hydrogen or sulpho, with a thioester of the formula (III):
    Figure US20040063682A1-20040401-C00012
  • in which Het is as above and R[0021] 10 has any of the values of R1. U.S. Pat. No. 4,652,651 discloses that where R10 is a lower alkoxycarbonyl-lower alkyl group, for example the t-butoxycarbonylmethyl group, this can be converted, if desired, into the corresponding carboxylower alkyl group by treatment with a strong acid such as trifluoroacetic acid (optionally in the presence of anisole), hydrochloric acid or p-toluenesulphonic acid at a low temperature such as −10° C. to room temperature.
  • There remains a need in the art for a process of making Aztreonam which does not require anhydrous reaction conditions and which also enables high yield and high purity. The present invention answers this need. [0022]
    • SUMMARY OF THE INVENTION
  • The invention is based on the discovery that Aztreonam can be produced by reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid with aqueous acid. The process of the invention, enables yields of between 70-75% and purities above 98%, preferably above 99%. The inventive aqueous process is advantageous over the prior art anhydrous processes in that the reaction conditions are more mild, there is no need to clean the final product and there is no need to keep the system dry. Thus, the aqueous process is less expensive than the anhydrous processes. [0023]
  • The present invention is directed to a process for preparing [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid by hydrolyzing the ester group of [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid. The hydrolysis may be effected by reacting the ester with aqueous acid, at elevated temperatures. [0024]
  • One reaction scheme for carrying out the process is shown below: [0025]
    Figure US20040063682A1-20040401-C00013
    • DETAILED DESCRIPTION OF THE INVENTION
  • The invention is directed to a process for making Aztreonam comprising reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid also known as (t-Bu Aztreonam and Aztreonam t-butyl ester) with an aqueous acid at elevated temperatures. [0026]
  • The aqueous acid is preferably a mineral acid, such as hydrochloric acid or sulfuric acid, of various concentration. The aqueous mineral acid is preferably more concentrated than 0.1 mol/l. Preferably, the aqueous acid is a 1:1 v/v HCl:water mixture. Aqueous trifluoroacetic acid may also be used in various concentrations. [0027]
  • The hydrolysis reaction is carried out at elevated temperatures, preferably 40° C. or greater, more preferably between 50 and 80° C., and most preferably between 60 and 70° C. [0028]
  • The Aztreonam t-butyl ester can be obtained by reacting Azetidin, (3S,4S)-3-Amino-4-methyl-2-oxo-azetidine-1-sulfonic acid, with TAEM ((Z)-2-(2-Aminothiazole-4-yl)-2-(t-butoxycarbonyl)-isopropoxyimino acetic acid, benzothiazole-2-yl-thiolester), as illustrated in Examples 1 and 2. [0029]
  • The present invention is illustrated in further detail with reference to the following non-limiting examples.[0030]
    • EXAMPLE 1
  • 5.4 g Azetidin is dissolved in 20 ml acetonitrile (or dimethyl formamide) with the assistance of 5 ml of triethylamine at room temperature. The solution is cooled to 0° C. A solution of 4 g TAEM in 25 ml THF is added with magnetic stirring. If the color disappears, 8 g TAEM in 50 ml THF is added. After 10 minutes, another 4.1 g TAEM in 25 ml THF is added. The solution is stirred at 0° C. for an additional hour. The pH is adjusted to about 4-5 with a freshly prepared TFA solution (TFA-THF 1:4, V/V). Being careful not to evaporate the acetonitrile, the THF is evaporated (weight loss is about 90 g) at 30° C. under vacuum. The remaining residue is diluted with 200 ml ethylacetate and then extracted with 100 ml and then 50 ml of distilled water. The aqueous extracts are combined and washed twice with 50 ml ethylacetate after readjustment of the pH to about 4-5. The dissolved ethylacetate is removed from the aqueous phase by vacuum at 30° C. 10-15 g KCl (or NaCl) is dissolved. The solution is acidified with HCl solution (cc. HCl-distilled water 1:4, V/V) with stirring (approx. 10 ml). The solution is cooled to 0° C. with slow stirring and crystallization occurs. The resulting suspension is refrigerated overnight (at about 5° C.). The suspension is filtered on a glass filter, and the crystals are washed with chilled water. The washed crystals are dried at room temperature. The product, Aztreonam t-butyl ester, is about 12.5-13 g white solid, which is sufficiently pure for the next step. [0031]
    • EXAMPLE 2
  • 65 g Azetidine is dissolved in a mixture of 240 ml acetonitrile and 60 ml triethylamine. When dissolution is complete, TAEM is added in four portions. The suspension is stirred for 20-30 min, then diluted with 500 ml EtOAc and 500 ml water and stirred for 5-10 min. The pH of the emulsion is set to 5 with 2.4 M HCl solution. After the phases separate, the pH of the aqueous phase is checked. If the pH is between 4.20 and 5.30, the two phases are filtered and separated, otherwise more HCl is added. The upper phase is diluted with 900 ml ethylacetate and extracted with 2×500 ml water (faster phase separation). The combined aqueous phase is diluted with 500 ml water and washed with 2×500 ml ethylacetate. The dissolved ethylacetate is removed from the aqueous phase by vacuum. The aqueous phase is acidified further to pH 2 with 2.4 M HCl solution. The solution is stirred and cooled. Crystallization starts soon. The suspension is stirred and cooled to 0° C., stirring at this temperature overnight. The suspension is filtered, washed with chilled water, dried at 38° C. in air-circulated oven for 3 h. The yield is approx. 116-120 g of Aztreonam t-butyl ester. [0032]
    • EXAMPLE 3
  • Aztreonam t-butyl ester (113.6 g, 0.231 mol) is suspended in 975 ml water at 60° C. with stirring and 325 ml trifluoroacetic acid is added. The solution is stirred for 60 min., then it is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 240 ml chilled water and filtered again. The filtrate is re-suspended in 360 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 61.6 g Aztreonam (water content: 15-16%). [0033]
    • EXAMPLE 4
  • Aztreonam t-butyl ester (18.0 g, 0.0366 mol) is suspended in 144 ml water at 60° C. with stirring and 40 ml aqueous hydrochloric acid (1:1, V/V) is added. The solution is stirred for 60 min, then 37 ml 5.4 M NaOH solution is added. The solution is cooled slowly using an ice-water bath. After the product precipitates, the suspension is refrigerated overnight. The product is filtered on a glass-filter, suspended in 50 ml chilled water and filtered again. The filtrate is re-suspended in 70 ml cold acetone and filtered. The latter step is repeated and the product is dried at room temperature to yield 8.3 g Aztreonam (water content: 15-16%). The crude Aztreonam is crystallized. [0034]
    • EXAMPLE 5
  • Aztreonam t-butyl ester (100.00 g, Assay as is: 97.2%, 0.19796 mol)) is suspended in a mixture of 450 ml water and 5 ml trifluoroacetic acid. The suspension, which slowly becomes clear, is heated to 58° C. with stirring and 100 ml trifluoroacetic acid is added. The solution is stirred for 105 min at 60-63° C. The solution is added to chilled water (450 ml) with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 18 hours. The product is filtered on a glass-filter and washed with 300 ml chilled water. The product is suspended in 650 ml chilled water, then filtered and washed with 300 ml cold acetone. The product is suspended in 400 ml cold acetone and filtered and dried in an air-ventilation oven at 30° C. for 30 min. Yield: 66.6 g (63%, according to assays) Aztreonam (Assay: 100.5%, water content: 18.0%). [0035]
  • HPLC Impurity Profile: [0036]
  • Aztreonam: 99.22% [0037]
  • Aztreonam t-butyl ester: 0.44% [0038]
  • HPLC Impurity Profile of Sample from Reaction Mixture: [0039]
  • Aztreonam: 82.20% [0040]
  • Aztreonam t-butyl ester: 0.43% [0041]
  • Aztreonam, open-chained: 7.22% [0042]
  • Other main degradation product (RRT=0.56): 5.24% [0043]
    • EXAMPLE 6
  • Aztreonam t-butyl ester (27.11 g, Assay as is: 96.5%, 0.05328 mol) is suspended in a mixture of 122 ml water and 1.35 ml cc. HCl. The suspension is heated to 62° C. with stirring and 30 ml cc. HCl is added. The suspension, which becomes clear after approx. 15 min, (then the product starts to precipitate), is stirred for 30 min at 63-65° C. Chilled water (162 ml) is added with efficient stirring and the resulting slurry is cooled further to 25° C. After two hours it is cooled to 0° C. and stirred for 2 hours. The product is filtered on a glass-filter, washed twice with 120 ml chilled water, twice with 125 ml cold acetone and filtered. The product is dried at room temperature overnight. Yield: 19.44 g (72%, according to assays) Aztreonam (Assay: 100.1%, water content: 14.4%). [0044]
  • HPLC Impurity Profile: [0045]
  • Aztreonam: 99.65% [0046]
  • Aztreonam t-butyl ester: 0.21% [0047]
  • HPLC Impurity Profile of Sample from Reaction Mixture: [0048]
  • Aztreonam: 89.43% [0049]
  • Aztreonam t-butyl ester: 0.26% [0050]
  • Aztreonam, open-chained: 4.70% [0051]
  • Other main degradation product (RRT=0.56): 1.47% [0052]
  • Having thus described the invention with reference to particular preferred embodiments and illustrated it with examples, those of skill in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. [0053]

Claims (15)

What is claimed is:
1. A process for making Aztreonam comprising reacting [3S-[3α(Z),4β]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (t-Bu Aztreonam) with an aqueous acid.
2. The process of claim 1, wherein the acid is a mineral acid.
3. The process of claim 2, wherein the mineral acid is selected from the group consisting of hydrochloric acid, sulfuric acid and trifluoroacetic acid.
4. The process of claim 2, wherein the aqueous mineral acid has a concentration greater than 0.1 mole/liter.
5. The process of claim 3, wherein the mineral acid is hydrochloric acid.
6. The process of claim 3, wherein the mineral acid is trifluoroacetic acid.
7. The process of claim 1, wherein the aqueous acid is a 1:1 v/v HCl:water mixture.
8. The process of claim 1, wherein the reaction takes place at a temperature greater than about 40° C.
9. The process of claim 8, wherein the temperature is between about 50° C. to about 80° C.
10. The process of claim 9, wherein the temperature is between about 60° C. to about 70° C.
11. The process of claim 1, wherein the yield of Aztreonam is at least about 70%.
12. The process of claim 1, wherein the purity of Aztreonam, as measured by HPLC, is greater than about 98%.
13. The process of claim 1, wherein the purity of Aztreonam, as measured by HPLC, is greater than about 99%.
14. Aztreonam produced by the process of any of claims 1-10, which has a purity as measured by HPLC, of greater than about 98%.
15. Aztreonam produced by the process of any of claims 1-10, which is hydrated.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050032775A1 (en) * 2003-07-02 2005-02-10 Viktor Gyollai Aztreonam L-lysine and methods for the preparation thereof
US7452991B2 (en) 2003-05-15 2008-11-18 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Aztreonam β polymorph with very low residual solvent content

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2606901A1 (en) 2005-05-09 2006-11-16 Sicor Inc. Process for making aztreonam
WO2007083187A2 (en) * 2006-01-16 2007-07-26 Orchid Chemicals & Pharmaceuticals Limited An improved process for the preparation of monobactam antibiotic
CN101412715B (en) * 2008-12-16 2010-04-14 海南百那医药发展有限公司 Aztreonam compound and preparation thereof
CN102127068B (en) * 2010-12-31 2012-08-29 山西普德药业股份有限公司 Method for synthesizing aztreonam compound
CN102311431B (en) * 2011-08-30 2014-12-10 海南海药股份有限公司 Method for preparing anhydrous beta-aztreonam
CN105017241B (en) * 2015-06-24 2018-03-06 山东罗欣药业集团股份有限公司 A kind of aztreonam compound and its preparation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529698A (en) * 1981-01-19 1985-07-16 E. R. Squibb & Sons, Inc. Process for preparing a 2-oxo-1-azetidinesulfonic acid salt
US4923998A (en) * 1977-03-14 1990-05-08 Fujisawa Pharmaceutical Company, Ltd. Cephem and cepham compounds and processes for preparation thereof
US20040062721A1 (en) * 2000-12-27 2004-04-01 Montgomery Alan Bruce Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections
US20050014739A1 (en) * 2003-05-15 2005-01-20 Viktor Gyollai Aztreonam beta polymorph with very low residual solvent content
US20050032775A1 (en) * 2003-07-02 2005-02-10 Viktor Gyollai Aztreonam L-lysine and methods for the preparation thereof

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775670A (en) 1980-09-29 1988-10-04 E. R. Squibb & Sons, Inc. 2-oxo-1-azetidinesulfonic acid salts
US4946838A (en) 1981-07-13 1990-08-07 E. R. Squibb & Sons, Inc. Crystalline anhydrous aztreonam
CA1181075A (en) 1981-07-13 1985-01-15 David M. Floyd CRYSTALLINE ANHYDROUS FORM OF [3-S-[3.alpha.(Z),4 .beta.]]-3-[[(2-AMINO-4-THIAZOLYL) [(1-CARBOXY-1-METHYLETHOXY)IMINO]ACETYL] AMINO]-4-METHYL-2-OXO-1-AZETIDINESULFONIC ACID
US4652651A (en) 1983-05-31 1987-03-24 Hoffmann-La Roche Inc. Process for the manufacture of 1-sulpho-2-oxoazetidine carboxylic acid intermediates via catalytic ester cleavage
US4826973A (en) 1984-07-20 1989-05-02 E. R. Squibb & Sons, Inc. Delta form of aztreonam and preparation thereof
CA1339136C (en) 1987-07-01 1997-07-29 Sailesh Amilal Varia Amorphous form of aztreonam
US5254681A (en) * 1989-08-02 1993-10-19 Consiglio Nazionale Delle Ricerche Process for preparing monobactames and their intermediate product
US5194604A (en) * 1990-06-29 1993-03-16 E. R. Squibb & Sons, Inc. Process and intermediates for beta-lactams having aminothiazole(iminooxyacetic acid)acetic acid sidechains
PL165700B1 (en) 1991-10-15 1995-01-31 Pan Method of obtaining z2/2-aminothiazolyl-4/-2/-t-butoxycarbonyl-1-methylethoxyimine/ acetic acid
BRPI0116757B8 (en) 2000-12-27 2021-05-25 Corus Pharma Inc composition, formulation and product containing aztreonam and its use for inhaled application
CN1545514A (en) 2001-08-27 2004-11-10 阿拉宾度药业有限公司 Production method for beta type crystal anhydrous ammonia leaven
AU2002356646A1 (en) 2002-12-11 2004-06-30 Pari Gmbh Pharmaceutical compositions for the pulmonary delivery of aztreonam

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4923998A (en) * 1977-03-14 1990-05-08 Fujisawa Pharmaceutical Company, Ltd. Cephem and cepham compounds and processes for preparation thereof
US4529698A (en) * 1981-01-19 1985-07-16 E. R. Squibb & Sons, Inc. Process for preparing a 2-oxo-1-azetidinesulfonic acid salt
US20040062721A1 (en) * 2000-12-27 2004-04-01 Montgomery Alan Bruce Inhalable aztreonam lysinate formulation for treatment and prevention of pulmonary bacterial infections
US20050014739A1 (en) * 2003-05-15 2005-01-20 Viktor Gyollai Aztreonam beta polymorph with very low residual solvent content
US20050032775A1 (en) * 2003-07-02 2005-02-10 Viktor Gyollai Aztreonam L-lysine and methods for the preparation thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7452991B2 (en) 2003-05-15 2008-11-18 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Aztreonam β polymorph with very low residual solvent content
US20050032775A1 (en) * 2003-07-02 2005-02-10 Viktor Gyollai Aztreonam L-lysine and methods for the preparation thereof
US7262293B2 (en) 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof

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